Glucose limitation activates AMPK coupled SENP1-Sirt3 signalling in mitochondria for T cell memory development

Jianli He, Xun Shangguan, Wei Zhou, Ying Cao, Quan Zheng, Jun Tu, Gaolei Hu, Zi Liang, Cen Jiang, Liufu Deng, Shengdian Wang, Wen Yang, Yong Zuo, Jiao Ma, Rong Cai, Yalan Chen, Qiuju Fan, Baijun Dong, Wei Xue, Hongsheng Tan, Yitao Qi, Jianmin Gu, Bing Su, Y. Eugene Chin, Guoqiang Chen, Qi Wang (), Tianshi Wang () and Jinke Cheng ()
Additional contact information
Jianli He: Shanghai Jiao Tong University School of Medicine
Xun Shangguan: Renji Hospital Affiliated, Shanghai Jiao Tong University School of Medicine
Wei Zhou: Shanghai Jiao Tong University School of Medicine
Ying Cao: Shanghai Jiao Tong University School of Medicine
Quan Zheng: Shanghai Jiao Tong University School of Medicine
Jun Tu: Shanghai Jiao Tong University School of Medicine
Gaolei Hu: Shanghai Jiao Tong University School of Medicine
Zi Liang: Shanghai Jiao Tong University School of Medicine
Cen Jiang: Shanghai Jiao Tong University School of Medicine
Liufu Deng: Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Shengdian Wang: Institute of Biophysics, Chinese Academy of Sciences
Wen Yang: Shanghai Jiao Tong University School of Medicine
Yong Zuo: Shanghai Jiao Tong University School of Medicine
Jiao Ma: Shanghai Jiao Tong University School of Medicine
Rong Cai: Shanghai Jiao Tong University School of Medicine
Yalan Chen: Shanghai Jiao Tong University School of Medicine
Qiuju Fan: Shanghai Jiao Tong University School of Medicine
Baijun Dong: Renji Hospital Affiliated, Shanghai Jiao Tong University School of Medicine
Wei Xue: Renji Hospital Affiliated, Shanghai Jiao Tong University School of Medicine
Hongsheng Tan: Shanghai Jiao Tong University School of Medicine
Yitao Qi: Shaanxi Normal University
Jianmin Gu: Zhongshan Hospital, Fudan University
Bing Su: Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine
Y. Eugene Chin: Institutes of Biology and Medical Sciences, Soochow University Medical College
Guoqiang Chen: Shanghai Jiao Tong University School of Medicine
Qi Wang: Renji Hospital Affiliated, Shanghai Jiao Tong University School of Medicine
Tianshi Wang: Shanghai Jiao Tong University School of Medicine
Jinke Cheng: Shanghai Jiao Tong University School of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract Metabolic programming and mitochondrial dynamics along with T cell differentiation affect T cell fate and memory development; however, how to control metabolic reprogramming and mitochondrial dynamics in T cell memory development is unclear. Here, we provide evidence that the SUMO protease SENP1 promotes T cell memory development via Sirt3 deSUMOylation. SENP1-Sirt3 signalling augments the deacetylase activity of Sirt3, promoting both OXPHOS and mitochondrial fusion. Mechanistically, SENP1 activates Sirt3 deacetylase activity in T cell mitochondria, leading to reduction of the acetylation of mitochondrial metalloprotease YME1L1. Consequently, deacetylation of YME1L1 suppresses its activity on OPA1 cleavage to facilitate mitochondrial fusion, which results in T cell survival and promotes T cell memory development. We also show that the glycolytic intermediate fructose-1,6-bisphosphate (FBP) as a negative regulator suppresses AMPK-mediated activation of the SENP1-Sirt3 axis and reduces memory development. Moreover, glucose limitation reduces FBP production and activates AMPK during T cell memory development. These data show that glucose limitation activates AMPK and the subsequent SENP1-Sirt3 signalling for T cell memory development.

Date: 2021
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DOI: 10.1038/s41467-021-24619-2

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